(288) Cardiovascular Efficacy and Safety of Incretin Mimetics and Sodium-Glucose Co-Transporter 2 Inhibitors as Add-on to Metformin Monotherapy in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of RCTs

Publication Number: 619

Background: Incretin mimetics and Sodium-glucose co-transporter-2 inhibitors (SGLT2Is) have been shown to minimize cardiovascular events in people with type 2 diabetes mellitus (T2DM) in recent studies. These new anti-diabetic medication classes have cardiovascular advantages and risks as a supplement to metformin monotherapy that have yet to be determined.

Objectives: To systematically synthesize the evidence on the comparative cardiovascular efficacy and safety of incretin mimetics and SGLT2Is as add-on to metformin monotherapy in patients with T2DM.

Methods: A literature search was performed in PubMed, Cochrane CENTRAL, and ICTRP from inception to 30th April 2022. The key search terms used were (“Diabetes Mellitus, Type 2” OR “Diabetes Mellitus, Type 2/drug therapy”) AND (“Dipeptidyl-Peptidase IV Inhibitors” OR “Glucagon-Like Peptide-1 Receptor/agonists” OR “Sodium-Glucose Co-Transporter-2 Inhibitors”) AND (“Metformin”). Patients with T2DM who had previously been treated with metformin monotherapy and were given either Glucagon-like peptide-1 receptor agonists (GLP-1 RA), Dipeptidyl peptidase-4 (DPP-4) inhibitors or SGLT2Is as add-on medications were included in the study. The Fixed or Random-effects model was used based on the heterogeneity identified by using the I² statistic and Cochran's Q test.

Results: Out of 4357 non-duplicate RCTs identified through database searching, a total of 16 studies with 16,843 patients were included in this study. The pooled analysis revealed a significant reduction in cardiovascular death (OR=0.78, 95% Cl 0.63, 0.98; P=0.03), all-cause mortality events (OR = 0.82, 95% Cl 0.69, 0.97; P = 0.02) and LDL cholesterol (MD = -0.07, 95% Cl -0.14, -0.01; P = 0.03) with GLP1-RAs–metformin add-on therapy compared to control group. All the three antidiabetic drug classes significantly reduced the HbA1C level (MD = -0.53, 95% Cl -0.68, -0.38; P<0.000001) when compared to the control group. For serious adverse events and hypoglycemia, tofogliflozin ranked first. Lixisenatide had the lowest risk of non-fatal myocardial infarction, while placebo had the greatest according to the SUCRA (Surface Under the Cumulative Ranking Curve).

Conclusions: When added to metformin monotherapy, GLP1-RAs show clear superiority in reducing cardiovascular and all-cause mortality among new antidiabetic drug classes. DPP4is, with the exception of lowering HbA1C levels, did not reduce the risk of any of these outcomes, making it inferior to the other two drug classes.